Dendrites can be damaged in stroke, seizure and traumatic brain injury. It is not known whether dendrite regeneration is a normal part of recovery from any of these events. Dendrite regeneration may be an unexplored process to target for improving recovery. Two major impediments prevent assessment of the importance of dendrite regeneration in nervous system repair: 1. Dendrite regeneration can currently be studied only by tracking individual neurons over time, 2. The machinery that mediates dendrite regeneration is completely unknown. In this proposal we propose to break through these impediments. Molecular markers are required to study dendrite regeneration in complex tissues after they are damaged. The first aim of this proposal is to identify a molecular signature of dendrite regeneration that can be used to pinpoint when and where it occurs in any tissue in any animal. To define a dendrite regeneration signature we will isolate individual neurons undergoing dendrite regeneration from whole animals. We will compare transcriptomes of these cells to uninjured neurons and neurons undergoing axon regeneration. We will select a set of 10-15 genes that are highly upregulated in dendrite regeneration and determine whether they are also upregulated in a different neuron type during dendrite regeneration. After this refinement, we will test commercially available antibodies to determine which markers will be most useful as part of a signature set to identify cells regenerating dendrites. With this marker set, it will be possibleto determine whether dendrite regeneration is initiated by stroke, seizure or traumatic brain injury. To determine where dendrite regeneration is important, and to understand how we might manipulate it to change injury outcome, we need to know how it works. The second aim is focused on identifying key regulators of dendrite regeneration. Unbiased functional approaches in Drosophila, as well as a screen based on transcriptome data, will be used to identify proteins that control dendrite regeneration. As no genes required for dendrite regeneration have yet been identified this aim is necessarily exploratory. By using three approaches in a model system with phenomenal genetic tools we will maximize our chances of identifying the first pieces of the dendrite regeneration machinery. Dendrite regeneration is potentially a major player in the recovery of the damaged nervous system. Unlike axon regeneration, no molecular players and very little basic information about dendrite regeneration is known. By identifying the first molecules that are associated with and required for dendrite regeneration, this project will open a new field for mechanistic studies.